Cerebral white matter (WM) is damaged in many neurologic disorders, including focal ischemia, perinatal brain injury, trauma, and multiple sclerosis. During the previous funding period, we and others established that oligodendrocytes (OLs) are highly vulnerable to over activation of AMPA/kainate (AMPA/KA) glutamate receptors. Unexpectedly, we found that AMPA/KA antagonists during oxygen-glucose deprivation protect axons as well as OLs, in oligodendrocyte-axon co-cultures and in WM brain slices. Since isolated axons are not vulnerable to glutamate receptor activation, the mechanisms of excitotoxic axon injury remain unknown. We will examine the hypothesis that over activation of AMPA/KA receptors on oligodendrocytes during oxygen-glucose deprivation contributes to damage of myelinated axons, and this involves release of reactive oxygen species (ROS). We have developed two new models to study these cellular interactions (a) a cell culture system in which isolated axons and oligodendrocytes are much more vulnerable to hypoxic and excitotoxic insults than either cell type alone, and (b) an acute brain slice model which allows measurement of white matter conduction together with visualization of axon and oligodendrocyte morphology. Using these models we will determine the role of oligodendrocyte glutamate receptor activation in axon injury, and assess potential injury pathways involving reactive oxygen species. Results of these studies may suggest treatment approaches for diseases, which share common pathology in central white matter.